13-48303995-C-T

Variant names:

• chr13-48303995-C-T
• rs776175164
• NM_000321.3:c.83C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6 BS2_Supporting

The NM_000321.3(RB1):​c.83C>T​(p.Pro28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 1,345,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.83
• Publications: 5 publications found

Genes affected

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

RB1 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29314122).
• BP6: Variant 13-48303995-C-T is Benign according to our data. Variant chr13-48303995-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568297.
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.83C>T	p.Pro28Leu	missense	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.83C>T	p.Pro28Leu	missense	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.83C>T	p.Pro28Leu	missense	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.83C>T	p.Pro28Leu	missense	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.83C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.83C>T	p.Pro28Leu	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000446 AC: 6 AN: 1345604 Hom.: 0 Cov.: 31 AF XY: 0.00000603 AC XY: 4 AN XY: 663668

African (AFR) AF: 0.00 AC: 0 AN: 27118

American (AMR) AF: 0.00 AC: 0 AN: 30504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23684

East Asian (EAS) AF: 0.00 AC: 0 AN: 31510

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33500

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4042

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1063786

Other (OTH) AF: 0.00 AC: 0 AN: 55962

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Retinoblastoma (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.012	D
Polyphen		0.048	B
Vest4		0.31
MutPred		0.31		Gain of catalytic residue at P23 (P = 5e-04)
MVP		0.88
MPC		0.45
ClinPred		0.60	D
GERP RS		3.8
PromoterAI		0.14	Neutral
Varity_R		0.15
gMVP		0.17
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776175164; hg19: chr13-48878131;